Classifications

• • G—PHYSICS
  • G11—INFORMATION STORAGE
  • G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
  • G11B33/00—Constructional parts, details or accessories not provided for in the other groups of this subclass
  • G11B33/02—Cabinets; Cases; Stands; Disposition of apparatus therein or thereon
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
  • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D249/14—Nitrogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • G—PHYSICS
  • G11—INFORMATION STORAGE
  • G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
  • G11B20/00—Signal processing not specific to the method of recording or reproducing; Circuits therefor

Definitions

• This invention relates to novel triazolyl hydrazide derivatives, a process for the preparation thereof, pharmaceutical compositions comprising the same, to the use of them for the treatment of diseases and also for the preparation of pharmaceutical compositions suitable for the treatment of said diseases.
• new triazolyl hydrazide derivatives of the general formula (I) and pharmaceutically acceptable acid addition salts thereof ##STR2## wherein Q represents hydrogen or a heterocyclic group optionally substituted by a C 1-4 alkyl group; or a group of general formula SR 1 , wherein
• R 1 stands for C 1-4 alkyl or phenyl-(C 1-4 alkyl) optionally substituted by halogen, C 1-4 alkyl or nitro substitute therefor substituents; or Q represents a group of the formula NR 2 R 3 , wherein R 2 and R 3 each represents hydrogen, straight or branched chain C 1-6 alkyl or C 2-6 alkenyl;
• Z represents hydrogen or a group of the formula (C ⁇ X)--(N--R 4 )--NR 5 R 6 , wherein
• X stands for oxygen or sulfur
• R 4 , R 5 and R 6 each stand for hydrogen or C 1-4 alkyl
• R 7 stands for hydrogen, C 1-4 alkyl or phenyl-(C 1-4 alkyl) optionally substituted by one or more halogen atom(s), or an amino group optionally substituted by one or two C 1-4 alkyl substituents,
• R 8 stands for hydrogen or a group of the formula --(C ⁇ X)--(N--R 4 )--NR 5 R 6 , wherein X, R 4 , R 5 and R 6 are as stated above,
• the invention encompasses all the isomers or tautomeric forms of the compounds of the general formula (I).
• the new compounds according to the present invention exhibit excellent biological activity and low toxicity, e.g. they possess antianginal, tranquillant-sedative, cardiovascular, acid secretion inhibiting, gastric ulcer inhibiting and antimicrobial properties and they can be used as starting materials of other pharmaceutically active derivatives as well.
• heterocyclic group used throughout the specification relates to 4 to 8 membered heterocyclic groups which can be formed from compounds comprising independently one or more nitrogen and/or oxygen atom(s) or a group which can be obtained by condensing the same compounds with each other or with benzene. Such groups may be aromatic or partially or completely saturated and may carry one or more substituent(s).
• such groups e.g. the piperidyl, morpholinyl, piperazinyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyridazinyl, isoxazolyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, pyranyl or delta-3-piperidinlyl groups are mentioned.
• alkyl group relates to straight or branched chained saturated aliphatic hydrocarbon groups comprising 1 to 4 or 1 to 6 carbon atom(s), e.g. methyl, ethyl, i-butyl, t-butyl, n-hexyl, etc.
• C 2-6 alkenyl groups straight or branched chained alkenyl groups are mentioned (e.g. vinyl, allyl, 2-methyl-allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 2-pentenyl, 2-hexenyl etc.).
• halogen emcompasses the fluorine, chlorine, bromine and iodine atoms.
• the compounds of the general formula (I) are organic bases, so they can be transformed into acid addition salts.
• the pharmaceutically acceptable acid addition salts of the compounds of the general formula (I) can be formed with inorganic or organic acids.
• the hydrohalides such as hydrochlorides or hydrobromides
• carbonates sufates, acetates, fumarates, maleates, citrates, ascorbinates and tartrates can be mentioned.
• R 7 and Q are as defined above,
• R 10 represents hydrogen or a group of the formula (C ⁇ X)--XR 9 , with the proviso that if Y stands for hydrogen, R 10 represents a group of the formula (C ⁇ X)--XR 9 , wherein X and R 9 are as stated above, and if Y stands for a group of the formula (C ⁇ X)--XR 9 , R 10 represents hydrogen,
• reaction of the compounds of the general formulae (II) and (IIa), respectively, with hydrazine derivatives of the general formula (III) is carried out in a solvent inert toward the reactants.
• a solvent inert preferably methanol, 2-propanol, benzene or dimethyl sulfoxid are used.
• the reaction is performed at a temperature of 0° to 190° C., preferably between 20° and 110° C.
• the reaction is optionally carried out in the presence of a base, preferably an organic base.
• the isomerisation of the compounds of the general formula (Ia) into compounds of the general formulae (Ib), (Ic) and (Id) can be carried out in melt or by thermic rearrangement in a polar or dipolar aprotic solvent, preferably in acetic acid or dimethylformamide, at a temperature between 50° C. and 250° C., preferably at a temperature of 100° to 190° C.
• a mixture of the compounds of the general formulae (Ib), (Ic) and (Id) is produced, which can be separated into the individual isomers by methods known per se, e.g. by chromatography or fractional crystallization.
• reaction of the compounds of the general formulae (IV) and (V) can be performed in a polar solvent, preferably in an aqueous methanol solution, dimethylformamide or dimethyl sulfoxide, at a temperature between 0° and 190° C., preferably at a temperature of 50° to 160° C.
• the compounds of the general formula (I) obtained in form of a base can be converted into acid addition salts by methods known per se.
• the free bases are reacted with the corresponding acid in an inert solvent.
• the triazolyl esters of the general formula (II) used as starting materials are known compounds or can be produced on the analogy of known compounds (U.S. Pat. No. 3,686,301, DD patent specification No. 105,897).
• hydrazine derivatives of the general formula (III) are also known compounds (Belsteins Handbuch der Organischen Chemie 4, 546, Verlag Springer, Berlin, 1922; Ullmann: Encyklopadie der Technischen Chemie 13, p. 95, Verlag Chemie Weinheim, 1977).
• the carbohydrazide and thiocarbohydrazide of the general formula (IV) are commercially available products.
• the compounds of the general formula (V) are also commercial products or can be prepared as described in Hungarian patent specification No. 184,743.
• the compounds of the general formula (I) are only very slightly toxic and show excellent biological properties. They exert antianginal, tranquillant-sedative, cardiovascular, acid secretion inhibiting, gastric ulcer inhibiting and antimicrobial effects.
• the test was carried out on rats weighing 180 to 220 g.
• the animals were narcotised with chloralese-urethane (70-700 mg/kg ip.).
• the ECG was registered with needle electrodes in standard II leading.
• the experimental coronaria insufficiency was induced with vasopressin (1 NE/kg i.v.).
• the height of wave T was measured before and after the administration of vasopressin in both the control and treated groups.
• Test compounds were administered intravenously 2 minutes prior to the treatment with vasopressin The results are summarized in Table I.
• mice The tests were performed on mice. Groups consisting of 3 mice each were trated perorally with different doses of the compounds to be tested. One hour after the administration the test animals were placed in a Dews equipment. In this equipment the number of interruptions of infrared beam within 30 minutes was counted. The results obtained are shown in Table II.
• mice belonging to the CFLP strain (body weight 18 to 22 g, both male and female) were used, 6 animals for each dose.
• the test compounds were administered orally in a volume of 20 ml/kg. After treatment the animals were observed for a period of 14 days. The mice were kept in a plastic cage at room temperature. The animals get tap water and standard mouse fodder ad libitum. The toxicity data were determined with the aid of the method of Litchfield and Wilcoxon. The results are summarized in Table III.
• the compounds according to the invention posses valuable antimicrobial effect, especially against nonfermenting Gram-negative bacteria strains. So the compound of Example 9 inhibits, determined by agar diffusion method in a concentration of 500/ ⁇ g/hole, the bacteria strains listed in Table IV.
• compositions comprising as active ingredient at least one compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof in admixture with suitable inert solid or liquid pharmaceutical carriers.
• compositions of the present invention can be prepared by methods known per se by admixing the active ingredient with suitable inert solid or liquid carriers and bringing the mixture to galenic form.
• compositions of the present invention may be suitable for oral (e.g. tablet, pill, coated pill, dragee, solid or soft gelatine capsule, solution, emulsion or suspension), parenteral (e.g. injection solution) or rectal (e.g. suppository) administration.
• oral e.g. tablet, pill, coated pill, dragee, solid or soft gelatine capsule, solution, emulsion or suspension
• parenteral e.g. injection solution
• rectal e.g. suppository
• coated tablets, dragees and solid gelatine capsules e.g. lactose, corn starch, potatoe starch, talc, magnesium carbonate, magnesium stearate, calcium carbonate, stearic acid or the salts thereof, etc.
• soft gelatine capsules e.g. vegetable oils, fats, waxes or polyols of suitable consistency can be used.
• solutions and syrups e.g. water polyols (polyethylene glycol), saccharose or glucose can be used.
• the injection solutions can comprise e.g. water alcohols, polyols, glycerol or vegetable oils as carrier.
• the suppositories can be prepared with the aid of e.g. oils, waxes, fats or polyols of suitable consistency.
• the pharmaceutical formulations may comprise auxiliaries usually applied in pharmaceutical industry, e.g. wetting, sweetening agents, aroma substances, salts causing the change of osmotic pressure, buffers, etc.
• auxiliaries usually applied in pharmaceutical industry e.g. wetting, sweetening agents, aroma substances, salts causing the change of osmotic pressure, buffers, etc.
• the compounds of the general formula (I) can preferably be used in therapy orally in the form of tablets or capsules. Especially preferred are the capsules or tablets comprising 0.5 to 500 mg of active ingredient.
• the daily dose of the compounds of the general formula (I) can vary within wide ranges depending on several factors, e.g. on the activity of the active ingredient, the patient's condition and age, the severity of the disease, etc.
• the oral dose is generally 2 to 5000 mg/day, preferably 5 to 1000 mg/day. It has to be stressed that the above dose is only of informative character and the administered dose must always be determined by the physician therapeutist.
• a method for antianginal and/or gastric ulcer inhibiting treatment which comprises administering to the patient an effective amount of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof.
• Example 2 One proceeds as described in Example 1, with the difference that the mother liquor obtained after filtering the reaction mixture is allowed to stand for 2 days. The separated crystals are then filtered off and recrystallized from 2-propanol.
• Example 11 On proceeding as described in Example 11 the mother liquor obtained after filtering the reaction mixture is evaporated to dryness and the residue is recrystallized first from an aqueous ethanol solution then from acetonitrile.
• Example 14 One proceeds as described in Example 14, with the difference that the mother liquor obtained after filtration is allowed to stand for 2 days. Then the separated crystals are filtered off and recrystallized from a mixture of n-hexane and ether.
• Tablets having the following composition are prepared by methods known per se of the pharmaceutical industry:
• Ointments having the following composition are prepared by methods known per se of the pharmaceutical industry:
• the active ingredient is in the outer phase of the ointment, in dissolved state.
• Suppositories having the following composition are prepared by methods known per se of the pharmaceutical industry:
• Capsules having the following composition are prepared by methods known per se of the pharmaceutical industry:

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• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Veterinary Medicine (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Vascular Medicine (AREA)
• Urology & Nephrology (AREA)
• Signal Processing (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Reinforced Plastic Materials (AREA)
• Chemical And Physical Treatments For Wood And The Like (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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• 1989
  • 1989-10-25 HU HU895428A patent/HU206095B/hu not_active IP Right Cessation
• 1990
  • 1990-10-25 CN CN90108619A patent/CN1051173A/zh active Pending
  • 1990-10-25 JP JP2288248A patent/JPH03246282A/ja active Pending
  • 1990-10-25 YU YU201190A patent/YU47564B/sh unknown
  • 1990-10-25 FI FI905254A patent/FI905254A0/fi not_active IP Right Cessation
  • 1990-10-25 DE DE69019294A patent/DE69019294D1/de not_active Expired - Fee Related
  • 1990-10-25 EP EP90311690A patent/EP0425283B1/de not_active Expired - Lifetime
  • 1990-10-25 DE DE69019294T patent/DE69019294T4/de not_active Expired - Lifetime
  • 1990-10-25 RU SU904831604A patent/RU2039051C1/ru active
  • 1990-10-25 KR KR1019900017151A patent/KR910007895A/ko not_active Application Discontinuation
  • 1990-10-25 ES ES90311690T patent/ES2076334T3/es not_active Expired - Lifetime
  • 1990-10-25 BG BG93093A patent/BG51044A3/xx unknown
  • 1990-10-25 IL IL9612690A patent/IL96126A/en not_active IP Right Cessation
  • 1990-10-25 DK DK90311690.3T patent/DK0425283T3/da active
  • 1990-10-25 ZA ZA908557A patent/ZA908557B/xx unknown
  • 1990-10-25 IN IN851/MAS/90A patent/IN171608B/en unknown
  • 1990-10-25 AT AT90311690T patent/ATE122343T1/de not_active IP Right Cessation
  • 1990-10-25 PL PL90287506A patent/PL164879B1/pl unknown
  • 1990-10-25 US US07/604,488 patent/US5225410A/en not_active Expired - Fee Related

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